Method for treating cancer

ABSTRACT

A method for treating an adenocarcinoma excluding colon cancer, lung cancer and gastric cancer, comprising administering to a subject in need thereof and suffering from adenocarcinoma cancer, a pharmaceutically effective amount of at least one sulfoquinovosylacylglycerol compound represented by formula (1): 
                         
wherein R 101  represents an acyl residue of an unsaturated higher fatty acid, and R 102  represents a hydrogen atom, and/or at least one pharmaceutically acceptable salt thereof.

CROSS-REFERENCES TO RELATED APPLICATIONS

This is a Divisional Application of application Ser. No. 10/678,193,filed Oct. 2, 2003 (U.S. Pat. No. 7,148,200), which is a DivisionalApplication of application Ser. No. 09/934,874, filed Aug. 22, 2001(U.S. Pat. No. 6,770,629), which is a Continuation-in-Part Applicationof PCT Application No. PCT/JP00/00973, filed Feb. 21, 2000, which wasnot published under PCT Article 21(2) in English. The entire contents ofU.S. application Ser. No. 09/934,874, U.S. application Ser. No.10/678,193 and International application PCT/JP00/00973 are herebyincorporated by reference herein.

This application is based upon and claims the benefit of priority fromthe prior Japanese Patent Application No. 11-051397, filed Feb. 26,1999, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a medicament containing at least onecompound selected from the group consisting ofsulfopyranosylacylglycerol derivatives and pharmaceutically acceptablesalts thereof, as an active ingredient.

2. Description of the Related Art

Sulfur-containing glycolipids contained in natural products derivedfrom, e.g., algae and higher plants are known to have physiologicalactivities.

For example, in a document of Ohta et al. (Chemical & PharmaceuticalBulletin, 46(4), (1998)), it is described that a specificsulfoquinovosyldiacylglycerol derivative derived from red algae,Gigartina tenella, exhibits not only inhibitory activities against DNApolymerases α and β of higher organisms but also an HIV-derivedreverse-transcriptase inhibitory activity. Thesulfoquinovosyldiacylglycerol derivative disclosed in the Ohta documentis the one whose fatty acid that bonded, through ester-bond, at the C1carbon atom of the glycerol is an unsaturated fatty acid having 20carbon atoms with 5 double bonds, and whose another fatty acid thatbonded at the C2 carbon atom of the glycerol is a saturated fatty acidhaving 16 carbon atoms.

Furthermore, in a document of Mizushina et al. (Biochemical Pharmacology55, 537-541 (1998)), it is described that a mixture of specificsulfoquinovosyldiacylglycerol derivatives derived from a pteridophyteexhibits inhibitory activities against a calf DNA polymerase α and a ratDNA polymerase β, however, the mixture has no effect upon an HIV-derivedreverse-transcriptase activity.

On the other hand, in a document of Sahara et al. (British Journal ofCancer, 75(3), 324-332 (1997)), it is described that a fraction ofsulfoquinovosylmonoacylglycerols contained in an acetone extract from asea urchin intestine exhibits anticancer activities in-vivo andin-vitro. However, the sulfoquinovosylmonoacylglycerol fraction forwhich Sahara found the anticancer activities principally containssulfoquinovosylmonoacylglycerol having, bonded thereto through anester-bond, a saturated fatty acid with 16 carbon atoms. In thesulfoquinovosylmonoacylglycerol fraction,sulfoquinovosylmonoacylglycerols whose acyl moiety is that of anunsaturated fatty acid, are contained only in an extremely small amount.In addition, Sahara et al. have not yet investigated on anticanceractivities with respect to individual components contained in thesulfoquinovosylmonoacylglycerol mixture.

Furthermore, National Patent Publication No. 5-501105 describes that asulfoquinovosyldiacylglycerol derivative has an anti-virus activity.More specifically, it discloses that the derivative has an anti-HIV(human immunodeficiency virus) activity, however it does not disclosethat the derivative has DNA polymerase inhibitory activities andanticancer activities.

BRIEF SUMMARY OF THE INVENTION

An object of the present invention is to provide a medicament containinga sulfopyranosylacylglycerol derivative as an active ingredient.

The present inventors found that specific sulfopyranosylacylglycerolderivatives have medicinal activities and achieved the presentinvention. The present invention provides a medicament containing, as anactive ingredient, at least one compound selected from the groupconsisting of:

compounds represented by the following General Formula (1):

wherein R₁₀₁ represents an acyl residue of an unsaturated higher fattyacid, and R₁₀₂ represents a hydrogen atom or an acyl residue of anunsaturated higher fatty acid; and

pharmaceutically acceptable salts thereof.

Additional objects and advantages of the invention will be set forth inthe description which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. The objectsand advantages of the invention may be realized and obtained by means ofthe instrumentalities and combinations particularly pointed outhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate embodiments of the invention, andtogether with the general description given above and the detaileddescription of the embodiments given below, serve to explain theprinciples of the invention.

FIG. 1 shows anticancer activities of medicaments of the presentinvention against tumor cells.

FIG. 2 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

FIG. 3 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

FIG. 4 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

FIG. 5 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

FIG. 6 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

FIG. 7 shows an anticancer activity of a medicament of the presentinvention obtained by an animal test.

DETAILED DESCRIPTION OF THE INVENTION

In the specification, the term “carbon atoms” of a protecting grouprefers to the number of carbon atoms assuming that the protecting groupis unsubstituted. To be more specific, when the group represented by R⁶is a substituted alkyl group, its number of carbon atoms is that of thealkyl group itself, and the number of carbon atoms of the substituent onthe alkyl group is not counted. The same conditions are applicable tothe case where the protecting group is other than the alkyl group.

First, the sulfopyranosylacylglycerol derivative represented by GeneralFormula (1) and contained in the medicament of the present invention asan active ingredient will be more specifically explained.

In the sulfopyranosylacylglycerol derivative represented by GeneralFormula (1), the pyranose, which is a sugar skeleton constituting thepyranoside, may include α-D-quinovose (i.e., 6-deoxy-α-D-glucose),β-D-quinovose (i.e., 6-deoxy-β-D-glucose), α-D-fucose (i.e.,6-deoxy-α-D-galactose), β-D-fucose (i.e., 6-deoxy-β-D-galactose),α-D-rhamnose (i.e., 6-deoxy-α-D-mannose) and β-D-rhamnose (i.e.,6-deoxy-β-D-mannose).

The absolute configuration of the carbon (asymmetric carbon) at the2-position of the glycerol moiety may be either the S- orR-configuration.

The sugar skeleton of the pyranoside may be either a boat or chairconfiguration. However, the chair configuration is preferable in view ofstability.

In the sulfopyranosylacylglycerol derivative represented by GeneralFormula (1), R₁₀₁ represents an acyl residue of an unsaturated higherfatty acid.

The fatty acid giving the acyl residue represented by R₁₀₁ may be astraight-chain or branched-chain, unsaturated higher fatty acid. Fromthe viewpoint of using the compound represented by General Formula (1)as a medicament, the straight-chain unsaturated higher fatty acid ispreferably used.

The acyl residue of the straight-chain unsaturated higher fatty acid has14-26 carbon atoms (preferably even number of 14-26) with 1-6unsaturated bonds. The acyl residue of the straight-chain unsaturatedhigher fatty acid is represented by Formula: R—C (═O)—, where R is astraight-chain aliphatic unsaturated hydrocarbon group of 13-25 carbonatoms (preferably, an odd number of 13-25), and 1-6 unsaturated bondsare included in the hydrocarbon group.

In the sulfopyranosylacylglycerol derivative represented by GeneralFormula (1), R₁₀₂ represents a hydrogen atom or an acyl residue of anunsaturated higher fatty acid. In particular, R₁₀₂ preferably representsa hydrogen atom in consideration of an anti-cancer activity. When R₁₀₂is an acyl residue of the unsaturated higher fatty acid, the same fattyacid giving an acyl residue as defined in R₁₀₁ may be selected. R₁₀₁ andR₁₀₂ may be the same or different acyl residue.

Now, a method of preparing the sulfopyranosylacylglycerol derivatives ofthe present invention will be explained below. Thesulfopyranosylacylglycerol derivatives of the present invention can beprepared via (Step A) to (Step J) in accordance with the reactionprocedure shown in Scheme 1 below:

(Step A) The hydroxyl group bonded to the C1 carbon of the pyranose isconverted into a 2-propenyl group. (Step B) The hydroxyl group of the C6carbon of the pyranose is protected. (Step C) The hydroxyl groups bondedto the C2, C3 and C4 carbons of the pyranose are protected. (Step D) Theprotecting group of the C6 carbon previously protected is deprotected.(Step E) The hydroxyl group bonded to the C6 carbon is substituted witha group (for example, an alkylsulfonyloxy group or arylsulfonyloxygroup) which can be converted to a carbonylthio group. (Step F) The C6carbon is converted into a carbonylthio group. (Step G) The 2-propenylgroup bonded to the C1 carbon is converted into a diol. (Step H) Both ofthe hydroxyl groups or only the hydroxyl group at the 1-position of thediol thus obtained are/is esterified with a desired unsaturated higherfatty acid. (Step I) The carbonylthio group at the C6 carbon isconverted into a sulfonate salt. (Step J) The protecting groups of C2,C3 and C4 carbons of the sulfonate salt obtained are deprotected. As aresult, a salt of a sulfopyranosylacylglycerol derivative of the presentinvention can be produced. The salt thus obtained is subjected totitration with an acid such as hydrochloric acid to give thesulfopyranosylacylglycerol derivative of the present invention.

The aforementioned Steps A-J will be further explained in detail.

In Step A, the 2-propenylation is carried out by reacting the pyranosewith allyl alcohol in the presence of a strong acid, such astrifluoromethanesulfonic acid, usually at room temperature to 100° C.,preferably from 80 to 90° C., for a half day to two days. However, thereaction time varies depending upon the reaction conditions.

In Step B, the hydroxyl group bonded to the C6 carbon is protected toobtain the compound to which —OR⁶ is bonded at the C6 carbon (where R⁶represents an alkyl or substituted silyl group).

As the compound capable of protecting the hydroxyl group, a compound canbe used which can provide an alkyl group or substituted silyl group asthe R⁶ group.

Examples of the alkyl group represented by R⁶ preferably include bulkyand substituted alkyl groups. The substituents of the bulky andsubstituted alkyl groups include methyl and phenyl groups. The specificexamples of the substituted alkyl group include t-butyl and tritylgroups.

When the group represented by R⁶ represents a substituted silyl group,examples of substituents of the substituted silyl group include loweralkyl groups, preferably alkyl groups having 1-4 carbon atoms (forexample, methyl, ethyl, isopropyl and t-butyl groups); and aryl groups,preferably aryl groups having 6 carbon atoms (for example, a phenylgroup). The substituted silyl group represented by R⁶ preferablyincludes tri-substituted silyl groups, more preferably, at-butyldiphenylsilyl group.

When the compound 3, where R⁶ represents an alkyl group, is to beobtained, the protection of the hydroxyl group in Step B can be carriedout by adding a compound represented by R⁶—X (where R⁶ represents thealkyl group defined above, and X represents a halogen atom such aschlorine atom) to a solution of the compound 2 dissolved in an organicsolvent, such as anhydrous pyridine, and reacting the solution mixtureat room temperature in the presence of a catalyst such asp-dimethylaminopyridine (DMAP). As the compound R⁶—X, trityl chloride ispreferably used in view of manufacturability and reactivity.

When the compound 3, where R⁶ represents a substituted silyl group, isto be obtained, t-butyldiphenylsilyl chloride, for example, is used asthe compound R⁶—X, and the reaction is carried out usually in thepresence of a catalyst, such as imidazol, at room temperature for a halfday to two days. Note that the reaction time varies depending upon thereaction conditions.

In Step C, the hydroxyl groups bonded to the C2, C3 and C4 carbons areprotected and converted into —OR¹, —OR² and —OR³, respectively, where R¹to R³ independently represent an alkyl or substituted silyl group. Theprotection of these hydroxyl groups can be carried out by activating,with sodium hydride, the hydroxyl groups bonded to the C2, C3 and C4carbons of the compound 3 dissolved in an organic solvent, such asN,N-dimethylformamide (DMF), and reacting with the compound capable ofprotecting these hydroxyl groups at room temperature.

As the compound capable of protecting the hydroxyl groups, benzylbromide, p-methoxybenzyl bromide, t-butyldimethylsilyl chloride ortriethylsilyl chloride may be used.

The reaction using the compound capable of protecting the hydroxylgroups can be carried out under a suitable reaction condition for eachof the protecting groups.

The deprotection of the protecting group bonded to the C6 carbon in StepD may be carried out by reacting a solution of the compound 4 dissolvedin an organic solvent, such as methanol, in the presence of a catalyst,such as p-toluenesulfonic acid, generally for 12 hours to one day atroom temperature. The reaction time varies depending upon the reactionconditions.

In Step E, R⁴, that is, an alkylsulfonyl or arylsulfonyl group is bondedto the hydroxyl group at the C6 carbon of the compound 5, so that thehydroxyl group is converted into —OR⁴ to give the compound 6.

The reaction to give the —OR⁴ group is performed by adding a compoundhaving the alkylsulfonyl group or a compound having the arylsulfonylgroup to a solution of the compound 5 dissolved in an organic solvent,and reacting them. The alkyl group of the compound having thealkylsulfonyl group preferably includes unsubstituted alkyl groups, morepreferably, lower alkyl groups, much more preferably, alkyl groupshaving 1-2 carbon atoms (methyl and ethyl groups). The compound havingan alkylsulfonyl group can be represented by R^(4′)—X (where R^(4′)represents an alkylsulfonyl group, and X represents a halogen atom).Specific examples include methanesulfonyl chloride and ethanesulfonylchloride.

On the other hand, the aryl group of the compound having thearylsulfonyl group may include unsubstituted and substituted arylgroups, preferably aryl groups having 6 carbon atoms (e.g., a phenylgroup). In the case of the substituted aryl group, examples of thesubstituent thereof include p-methyl and p-methoxy groups. Examples ofthe compound having an arylsulfonyl group include compounds representedby R^(4″)—X (where R^(4″) represents an arylsulfonyl group, and Xrepresents a halogen atom). Specific examples include p-toluenesulfonylchloride, p-methoxybenzenesulfonyl chloride and benzenesulfonylchloride.

Of the compounds having an alkylsulfonyl or arylsulfonyl group, acompound having a tosyl group is preferably used from the viewpoint ofreaction facility.

In the reaction of Step E, as an organic solvent, pyridine ordichloromethane may be used.

The reaction mentioned above may be performed, as the case may be, inthe presence of a catalyst, such as DMAP, at room temperature for 2hours to one day. The reaction time varies depending upon the reactionconditions.

In Step F, the sulfonyloxy group (—OR⁴) of the compound 6 is replacedwith a carbonylthio group represented by —SC (═O)R⁵, where R⁵ representsa hydrogen atom, an alkyl or aryl group.

In the reaction, a compound capable of substituting the alkylsulfonyloxyor arylsulfonyloxy group of the compound 6 with the carbonylthio group,is allowed to react in an organic solvent to give a compound 7.Hereinafter, this compound will be referred to as“O-substituted→S-substituted compound”.

Examples of the O-substituted→S-substituted compound include alkalimetal salts and alkali earth metal salts of a thiocarboxylic acid.Examples of the thiocarboxylic acid include thioformic acid, lowerthiocarboxylic acids, preferably aliphatic thiocarboxylic acids eachhaving 1-5 carbon atoms in its aliphatic hydrocarbon moiety (forexample, thioacetic acid or thiopropionic acid), and aromaticthiocarboxylic acids each having 6-10 carbon atoms in its aromatichydrocarbon moiety (for example, thiobenzoic acid).

The alkali metal that forms a salt with the thiocarboxylic acid includespotassium and sodium. The alkali earth metal includes magnesium andcalcium.

Of the above-mentioned O-substituted→S-substituted compounds, salts ofthioacetic acid may be preferably used since a reaction can proceedstably and the sulfur atom can be easily oxidized in a later step.

Examples of an organic solvent used in the reaction include alcohols,preferably lower alcohols, (for example, methanol, ethanol andpropanol), N,N-dimethylformamide and dimethylsulfoxide.

The aforementioned reaction may be performed usually at room temperatureto the boiling point of a solvent to be used while stirring for one hourto one day. Note that the reaction time varies depending upon thereaction conditions.

The dihydroxylation of Step G may be performed by adding an oxidizingagent, such as osmium tetraoxide, to a solution of the compound 7dissolved in a solvent mixture, such as a mixture of t-butanol andwater, and then reacting the resultant mixture in the presence of are-oxidizing agent, such as trimethylamine N-oxide, at room temperaturefor one hour to one day. Note that the reaction time varies dependingupon the reaction conditions.

By the esterification of Step H, a sulfopyranosylacylglycerol derivativehaving a desired unsaturated higher fatty acid bonded, through anester-bond, to its glycerol moiety can be obtained.

This reaction can be carried out by adding an unsaturated higher fattyacid corresponding to a final product to a solution of the compound 8dissolved in a suitable organic solvent, such as dichloromethane, andthen reacting the resultant mixture, if necessary, in the presence of asuitable catalyst, such as ethyldimethylaminopropylcarbodiimide(EDCI)-DMAP.

In the reaction of Step H, as the fatty acid to be added, use may bemade of an unsaturated higher fatty acid whose acyl group is thatrepresented by R₁₀₁ of General Formula (1).

In the reaction of Step H, the compound 9 is obtained in the form of amixture of a diacylester and a monoacylester. The diacylester herein isrepresented by Formula (1) of the present invention where each of R₁₀₁and R₁₀₂ is an acyl residue of the unsaturated higher fatty acid added.The monoacylester herein has the acyl residue of the unsaturated higherfatty acid added, as the R₁₀₁ only. Two or more unsaturated higher fattyacids may be added, if desired, in the reaction of Step H. In this case,the resultant mixture contains diacylesters represented by GeneralFormula (1) where R₁₀₁ and R₁₀₂ are the same or different acyl residues,and monoesters having different acyl residues as R₁₀₁.

If necessary, the mixture of the monoesters and diesters can be isolatedfrom each other by, for example, chromatography, and subjected to thenext reaction Step I.

Furthermore, if desired, by reacting a monoester obtained in Step H witha fatty acid having a different acyl residue from the acyl residue(R₁₀₁) of the monoester, it is possible to obtain a diester where R₁₀₂and R₁₀₁ are different acyl residues. This additional esterificationstep may be performed under the same conditions as those of Step Hexcept that a different fatty acid is used.

In Step I, the conversion into a sulfonate salt can be carried out byadding an oxidizing agent, such as OXONE (2KHSO₅+KHSO₄+K₂SO₄) ormolybdenum oxidizing agent (for example, hexaammonium heptamolybdate),into a solution of the compound 9 dissolved in an organic solvent, whichis buffered with acetic acid and potassium acetate, and then allowingthe resultant mixture to react at room temperature.

The deprotection of the protecting groups bonded to carbons at the C2 toC4 carbons in Step J can be carried out by a method suitable for aprotecting group to be used and capable of maintaining a double bond ofthe unsaturated fatty acid. For example, when the protecting group is asilyl group, deprotection can be made by using acid catalyst (e.g.,trifluoroacetic acid).

Note that the pyranosyl moiety of a starting material usually takes α-and β-anomer configurations in a solution. Therefore, the product ineach step results in a mixture of α- and β-anomers. The mixture isseparated into α- and β-anomers by chromatography. Furthermore,depending upon a type of the sugar, it is helpful to carry out abenzilydenation after Step A, thereby to separate an anomer bycrystallization.

Now, we will explain the medicament of the present invention containingat least one compound selected from the group consisting ofsulfopyranosylacylglycerol derivatives of the present invention andpharmaceutically acceptable salts thereof, as an active ingredient.

The sulfopyranosylacylglycerol derivative serving as an activeingredient for the medicament of the present invention may be an isomerhaving quinovose, rhamnose or fucose as the pyranose constituting thepyranosyl moiety. The derivative may be an isomer in which the pyranosylmoiety is bonded to glyceridyl moiety with an α- or β-configuration. Thederivative may be an isomer regarding the asymmetric carbon at the C2carbon of the glyceridyl moiety. The medicament of the present inventionmay include one of these isomers alone or in combination of two or moreisomers as long as they do not adversely affect the activity.

In the present invention, the medicinal use includes a DNA polymeraseinhibitor and an anticancer agent.

Examples of the pharmaceutically acceptable salts employed in themedicament of the present invention include, but not limited to, a saltof a monovalent cation such as a sodium or potassium ion. Hereinafter,the compounds of the group consisting of sulfopyranosylacylglycerolderivatives and pharmaceutically acceptable salts thereof are sometimesreferred to as “medicinally active substance of the present invention”.

The medicinally active substance of the present invention can be orallyor parenterally administered. Medicinally active substance of thepresent invention can be combined with, for example, a pharmaceuticallyacceptable excipient or diluent depending on an administration routethereby to form a medicinal formulation.

The forms of the agent suitable for oral administration include, solid-,semi-solid, liquid- and gas-states. Specific examples include, but notlimited to, tablet, capsule, powder, granule, solution, suspension,syrup and elixir agents.

In order to formulate the medicinally active substance of the presentinvention into tablets, capsules, powders, granules, solutions orsuspensions, the substance is mixed with a binder, a disintegratingagent and/or a lubricant, and, if necessary, the resultant is mixed witha diluent, a buffer, a wetting agent, a preservative and/or a flavor, bya known method. Examples of the binder include crystalline cellulose,cellulose derivatives, cornstarch and gelatin. Examples of thedisintegrating agent include cornstarch, potato starch and sodiumcarboxymethylcellulose. Examples of the lubricant include talc andmagnesium stearate. Furthermore, additives such as lactose and mannitolmay also be used as long as they are used conventionally.

Moreover, the medicinally active substance of the present invention maybe administered in the form of aerosol or inhalant, which is prepared bycharging the active substance of liquid- or fine powder-form, togetherwith a gaseous or liquid spraying agent, and, if necessary, a knownauxiliary agent such as a wetting agent, into a non-pressurizedcontainer such as an aerosol container or a nebulizer. As the sprayingagent, a pressurized gas, for example, dichlorofluoromethane, propane ornitrogen may be used.

For parenteral administration, the medicinally active agent of thepresent invention can be injected by, for example, rectal administrationor injection.

For rectal administration, a suppository may be used. The suppositorymay be prepared by mixing the medicinally active substance of thepresent invention with an excipient that can be melted at bodytemperature but is solid at room temperature, such as cacao butter,carbon wax or polyethylene glycol, and molding the resultant material,by a known method.

For the administration by injection, the medicinally active agent of thepresent invention can be injected hypodermically, intracutaneously,intravenously or intramuscularly. An injection preparation may beformulated by dissolving, suspending or emulsifying the medicinallyactive substance of the invention into an aqueous or non-aqueous solventsuch as a vegetable oil, a synthetic glyceride with a fatty acid, anester of a higher fatty acid or propylene glycol by a known method. Ifdesired, a conventional additive such as a solubilizing agent, anosmoregulating agent, an emulsifier, a stabilizer or a preservative, maybe added to the preparation.

For formulating the medicinally active substance of the invention intosolutions, suspensions, syrups or elixirs, a pharmaceutically acceptablesolvent such as sterilized water for injection or normalizedphysiological saline solution may be used.

The medicinally active substance of the invention may be used togetherwith a pharmaceutically acceptable compound having another activity, toprepare a medicinal preparation.

The dose of the medicinally active substance of the present inventionmay be appropriately set or adjusted in accordance with anadministration form, an administration route, a degree or stage of atarget disease, and the like. For example, in the case of oraladministration, a dose of the medicinally active substance may be set at1-10 mg/kg body weight/day. In the case of administration by injection,a dose of the medicinally active substance may be set at 1-5 mg/kg bodyweight/day. In the case of rectal administration, a dose of themedicinally active substance may be set at 1-5 mg/kg body weight/day.However, the dose is not limited to these.

When the medicinally active substance of the present invention is usedas an anticancer agent, examples of cancers to be treated include thosehaving features of malignant tumors such as solid tumors includingadenocarcinoma, epithelioma, sarcoma, glioma, melanoma and lymphoma, anda fluid cancer such as leukemia.

EXAMPLES

The present invention will now be described by way of its Examples.However, the present invention is not limited to these Examples.

Synthesis Example

Preparation steps of a sulfopyranosylacylglycerol derivative will beshown in Scheme 2 by way of a sulfoquinovosylacylglycerol α derivative.

Scheme 2 is the same as those of Scheme 1 except for Steps B to E ofScheme 1. More specifically, in Scheme 2, Step m is employed instead ofStep B in Scheme 1. In Step m, compound (II) is reacted withbenzaldehyde to prepare a benzylidene derivative. By virtue of thisreaction, α-anomer is crystallized and separated.

In the reaction of Scheme 2, p-toluenesulfonyl chloride is reacted withcompound (IV) thereby to bond a tosyl group at C6 carbon thereof in Stepp, and then, the C2, C3 and C4 carbons are protected witht-butyldimethylsilyl groups (Step q). In this case, Step B of protectingthe C6 carbon by an alkyl or substituted silyl group, and Step D ofdeprotecting the C6 carbon in the process of Scheme 1 may be omitted,because of the stable nature of the tosyl group.

Furthermore, in Step h, a mixture of a monoester and diester isobtained. The monoester and the diester are separated from each other bychromatography and subjected to Step i, respectively.

Example 1 Route a: 1-O-(2-propenyl)-D-glucose (II)

One hundred grams of D-glucose (I) was added into 250 mL of allylalcohol and sufficiently dissolved therein. To the solution, 0.8 mL oftrifluoromethanesulfonic acid was gradually added under an ice-cooledcondition. Then, the solution was reacted in an oil bath at 80° C. for30 hours while stirring. At the stage where the reaction sufficientlyproceeded, the reaction mixture was neutralized with 1 mL oftrimethylamine and concentrated in vacuo. The thin layer chromatographydemonstrated a yield of about 60-70%.

Route m: 1-O-(2-propenyl)-4,6-O-benzylidene-α-D-glucose (III)

37.5 grams of the compound (II) was added to 210 mL of benzaldehyde anddissolved well. To the solution, 98 g of zinc chloride was added. Thereaction mixture was reacted at room temperature for 4 hours.Thereafter, the reaction mixture was added to 500 mL of hexane, and then100 mL of diluted sodium hydrogencarbonate was added. The reactionmixture was allowed to stand at 0° C. for 30 minutes to crystallize. Thecrystal was filtered with suction, and dissolved in 50 mL of ethanol.The solution was allowed to stand at 0° C. for 30 minutes forrecrystallization (yield: 21 g (68.1 mmol), recovery: 40.0%).

¹H NMR(300 MHz, CDCl₃+TMS); 7.51-7.49 (2H, m, Ar), 7.38-7.33 (3H, m,Ar), 5.98-5.85 (1H, m, —CH═CH₂), 5.51 (1H, s, Ar—CH), 5.31 (1H, dd,J=1.5&15.9, —CH═CH ₂), 5.23 (1H, dd, J=1.2&10.4, —CH═CH ₂), 4.90 (1H, d,J=3.9, H-1), 4.28-4.19 (2H, m, —CH₂ —CH═CH₂), 4.06-4.00 (1H, m, H-5),3.93 (1H, t, J=9.3,H-3), 3.87-3.78 (1H, m, H-6a), 3.70 (1H, t, J=10.2,H-2), 3.60 (1H, dd, J=3.8&9.2, H-6b), 3.47 (1H, t, J=9.3,H-4)

Route n: 1-O-(2-propenyl)-α-D-glucose (IV)

Into 260 mL of a solution of acetic acid and water (8:5), 10.7 g (34.7mmol) of the compound (III) was dissolved. The solution was reacted at100° C. for 1 hour, concentrated in vacuo, and purified by silica gelflash chromatography (dichloromethane:methanol=6:1) (yield: 6.3 g (28.6mmol), recovery: 82.4%).

¹H NMR (300 MHz, CD₃OD+TMS); 5.92-5.79 (1H, m, —CH═CH₂), 5.26-5.18 (1H,m, —CH═CH ₂), 5.07-5.03 (1H, m, —CH═CH ₂), 4.23-3.23 (7H, m)

Route p: 1-O-(2-propenyl)-6-O-(4-tolylsulfonyl)-α-D-glucose (V)

Into 200 mL of anhydrous pyridine, 6.3 g (28.6 mmol) of the compound(IV) was dissolved, and 195 mg of p-dimethylaminopyridine (DMAP) and 7.0g of p-toluenesulfonyl chloride were added. The solution was reacted for16 hours at room temperature while stirring. Thereafter, the reactionwas quenched by adding 20 mL of cold distilled water, and the reactionmixture was extracted with ethyl acetate (3×200 mL). The organic layerswere combined, neutralized to pH 4 with 1.0 M and 0.1 M hydrochloricacids, washed with brine (2×200 mL), dried over anhydrous sodiumsulfate, filtered, concentrated in vacuo, and purified by silica gelflash chromatography (dichloromethane:methanol=20:1) (yield: 8.6 mg(23.0 mmol), recovery: 83.8%).

¹H NMR (300 MHz, CDCl₃+TMS); 7.77 (2H, d,J=8.3,Ar at TsCH₃), 7.30 (2H,d, J=8.1 Ar at TsSO₂), 5.90-5.77 (1H, m, —CH═CH₂), 5.24 (1H, dd,J=1.4&17.2, —CH═CH ₂), 5.11 (1H, dd, J=1.2&12.4, —CH═CH ₂), 4.79 (1H, d,J=3.3, H-1), 4.38-3.38 (8H, m), 2.40 (3H, s, TSCH₃ )

Route q:2,3,4-tri-O-(t-butyldimethylsilyl)-1-O-(2-propenyl)-6-O-(4-tolylsulfonyl)-α-D-glucose(VI)

Into 25 mL of anhydrous dichloromethane, 11.2 g (29.9 mmol) of thecompound (V) was dissolved and 23.8 g of t-butyldimethylsilyltrifluoromethanesulfonate and 14.4 g of 2,6-lutidine were added. Thesolution was reacted under nitrogen flow for 16 hours while stirring.Thereafter, the reaction was quenched by adding 150 mL ofdichloromethane, and the reaction mixture was washed with brine (2×100mL), dried over anhydrous sodium sulfate, filtered, concentrated invacuo, purified by silica gel flash chromatography (hexane:ethylacetate=30:1) (yield: 19.6 g (27.4 mmol), recovery: 91.6%).

¹H NMR (300 MHz, CDCl₃+TMS); 7.83 (2H, d, J=8.3,Ar at TsCH₃), 7.29 (2H,d, J=8.0, Ar at TsSO₂), 5.92-5.79 (1H, m, —CH═CH₂), 5.21 (1H, dd,J=1.5&17.2, —CH═CH ₂), 5.11 (1H, d, J=10.4, —CH═CH ₂), 4.67 (1H, d,J=2.8, H-1), 4.30-3.44 (8H, m), 2.41 (3H, s, TSCH₃ ), 0.91-0.78 (27H, m,CH₃ at t-Bu), 0.13-−0.02 (18H, m, Si—CH₃ )

Route f:2,3,4-tri-O-(t-butyldimethylsilyl)-1-O-(2-propenyl)-6-deoxy-6-acetylthio-α-D-glucose(VII)

Into 20 mL of anhydrous ethanol, 7.9 g (11.0 mmol) of the compound (VI)was dissolved, and then 1.8 g of potassium thioacetate was added. Thesolution was reacted under reflux for 3 hours while stirring.Thereafter, the reaction was quenched by adding 100 mL of cold distilledwater, and the reaction mixture was extracted with ethyl acetate (3×200ml). The organic layers were combined, washed with brine (2×200 mL),dried over anhydrous sodium sulfate, filtered, concentrated in vacuo,and purified by silica gel flash chromatography (hexane:ethylacetate=50:1) (yield: 5.6 g (9.02 mmol), recovery: 82.0%).

¹H NMR (300 MHz, CDCl₃+TMS); 5.97-5.81 (1H, m, —CH═CH₂), 5.26 (1H, dd,J=1.6&17.2, —CH═CH ₂), 5.13 (1H, dd, J=1.6&10.4, —CH═CH ₂), 4.73 (1H, d,J=3.2, H-1), 4.32-3.42 (7H, m), 2.83 (1H, dd, J=9.8&13.3, H-6b),2.30(3H, s, SCOCH₃ ), 0.91-0.82 (27H, m, CH₃ at t-Bu), 0.12-−0.03 (18H,m, Si—CH₃ )

Route g:3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-acetylthio-α-D-glucopyranosyl]-glycerol(VIII)

Into a mixture of t-butanol:H₂O (=4:1), 5.6 g (9.02 mmol) of thecompound (VII) was dissolved and then 1.5 g of trimethylamine N-oxidedihydrate and 15 mL of 0.04 M solution of osmium tetraoxide in t-butanolwere added. The solution was reacted at room temperature for 22 hourswhile stirring. Thereafter, 15 g of activated charcoal was added, andthe reaction mixture was allowed to stand while stirring for 1.5 hoursto adsorb the osmium tetraoxide. After filtration with suction, thereaction was quenched by adding 200 mL of cold distilled water, andextracted with ethyl acetate (3×200 mL). The organic layers werecombined, washed with brine (2×300 mL), dried over anhydrous sodiumsulfate, filtered, concentrated in vacuo, and purified by silica gelflash chromatography (hexane:ethyl acetate=3:1→2:1) (yield: 5.2 g (7.94mmol), recovery: 88.0%).

¹H NMR (300 MHz, CDCl₃+TMS); 4.73 (1H, m, H-1 (R and S)), 4.12-3.40(10H, m), 2.86 (1H, dd, J=9.2&13.6, H-6b), 2.32 (3H, s, SCOCH₃ ),0.88-0.79 (27H, m, CH₃ at t-Bu), 0.08-−0.03 (18H, m, Si—CH₃ )

Route h:3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-acetylthio-α-D-glucopyranosyl]-1-O-oleoyl-glycerol(IX) and3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-acetylthio-α-D-glucopyranosyl]-1,2-di-O-oleoyl-glycerol(IX′)

Into 20 mL of anhydrous dichloromethane, 1.37 g (2.09 mmol) of thecompound (VIII) was dissolved and then 600 mg of EDCl, 26 mg of DMAP and660 mg of oleic acid were added. The solution was reacted at roomtemperature for 16 hours while stirring. Thereafter, the reaction wasquenched by adding 200 mL of dichloromethane, and washed with brine(2×100 mL), dried over anhydrous sodium sulfate, filtered, concentratedin vacuo, and purified by silica gel flash chromatography (hexane:ethylacetate=20:1→10:1→7:1) (yield of the diester: 772 mg (652 μmol) andyield of the monoester: 895 mg (974 μmol); recovery (both esters intotal) of 78.0%).

¹H NMR (300 MHz, CDCl₃+TMS); 5.32-5.28 (2H, m, —CH═CH—), 4.68 (1H, m,H-1(R and S)), 3.98-3.36 (10H, m), 2.81 (1H, dd, J=9.5&13.4, H-6b),2.32-2.27 (5H, m, OCOCH₂ & SCOCH₃ ), 1.98-1.93 (4H, m, CH₂ —CH═CH—CH₂ ),1.61-1.56 (2H, m, OCOCH₂CH₂ ), 1.28-1.23 (20H, br, —CH₂ —), 0.88-0.79(30H, m, CH₃ at t-Bu & CH₃ at Acyl), 0.09-−0.04 (18H, m, Si—CH₃ ) (NMRof the monoester)

Route i:3-O-[2,3,4-tri-O-(t-butyldimethylsilyl)-6-deoxy-6-sulfo-α-D-glucopyranosyl]-1-O-oleoyl-glycerolsodium salt (X)

Into 3.5 mL of glacial acetic acid, 21.4 mg (23.2 μmol) of the compound(IX: monoester) was dissolved and then 500 mg of potassium acetate and35.4 mg of OXONE were added. The mixture was reacted at room temperaturefor 6 hours while stirring. Thereafter, the reaction was quenched byadding 15 mL of cold distilled water, extracted with ethyl acetate (5×20mL). The organic layers were combined, neutralized with saturated sodiumhydrogencarbonate solution (5×70 mL), washed with brine(2×60 mL), driedover anhydrous sodium sulfate, filtered, concentrated in vacuo, andpurified by silica gel flash chromatography(dichloromethane:methanol=50:1→20:1). Thereafter, the reaction productwas further purified by high performance liquid chromatography (ODScolumn, methanol:water=80:20) (yield: 3.3 mg (3.49 μmol), recovery:15.0%).

1H NMR (300 MHz, CDCl₃+TMS); 5.16-5.14 (2H, br, —CH═CH—), 4.60 (1H, br,H-1(R and S)), 4.31-2.88 (11H, m), 2.17-2.13 (2H, br, OCOCH₂ ),1.82-1.80 (4H, br, CH₂ —CH═CH—CH₂ ), 1.42 (2H, br, OCOCH₂CH₂ ), 1.11(20H, br, —CH₂ —), 0.72 (30H, m, CH₃ at t-Bu & CH₃ at Acyl), −0.08 (18H,br, Si—CH₃ )

Route j: 3-O-(6-deoxy-6-sulfo-α-D-glucopyranosyl)-1-O-oleoyl-glycerolsodium salt (XI)

Into 7 mL of a solution of acetic acid, tetrahydrofuran, trifluoroaceticacid and water (3:1:0.4:1), 358.4 mg (378 μmol) of the compound (X) wasdissolved. The solution was reacted at room temperature for 16 hourswhile stirring, and the reaction mixture was extracted with ethylacetate (3×10 mL). The. organic layers were combined, washed with brine(2×20 mL), dried over anhydrous sodium sulfate, filtered, concentratedin vacuo, and purified by silica gel flash chromatography(dichloromethane methanol=10:1→dichloromethane:methanol:water=65:25:4)(yield: 138.1 mg (229 μmol), recovery: 62.7%).

¹H NMR (300 MHz, CD₃OD+TMS); 5.24-5.17 (2H, m, —CH═CH—), 4.69 (1H, m,H-1(R and S)), 4.18-2.75 (11H, m), 2.29-2.21 (2H, m, OCOCH₂ ), 1.94-1.90(4H, m, CH₂ —CH═CH—CH₂ ), 1.49 (2H, br, OCOCH₂CH₂ ), 1.20 (20H, br, —CH₂—), 0.78 (3H, t, J=6.3, CH₃ )

Example 2

The Steps h-j were carried out in the same manner as in Example 1 exceptthat myristoleic acid was used in place of oleic acid to synthesize3-O-(6-deoxy-6-sulfo-α-D-glucopyranosyl)-1-O-myristoleoly-glycerolsodium salt (yield: 118.7 mg (217 μmol), recovery: 59.8%).

Example 3

The same procedure as in Example 2 was repeated except that palmitoleicacid was used in place of oleic acid to synthesize3-O-(6-deoxy-6-sulfo-α-D-glucopyranosyl)-1-O-palmitoleoyl-glycerolsodium salt (yield: 142 mg (247 μmol), recovery: 67.7%).

Example 4

The same synthesis example as in Example 1, except that the compound(IX′: diester) was used in place of the compound (IX: monoester) in theroute i of preparing the compound (X) from the compound (IX), and amolybdenum oxidizer was used in place of OXONE, will be described.

13.1 mg (11.0 μmol) of the compound (IX′: diester) was dissolved in 0.5mL of dichloromethane and 0.5 mL of methanol. 50 μL of 0.06M solution ofhexaammonium heptamolybdate tetrahydrate ((NH₄)₆Mo₇0₂₄.4H₂O) in 30%hydrogen peroxide was further added thereto and stirred at roomtemperature for 50 hours. Thereafter, 10 mL of ethyl acetate was addedto the reaction solution, and the resultant solution was washed withsaturated sodium hydrogencarbonate solution (2×5 mL) and brine (2×5 mL),dried over anhydrous sodium sulfate, filtered, concentrated in vacuo,and purified by silica gel flash chromatography(dichloromethane:methanol=50:1→10:1). As a result, a colorless oilysubstance was obtained (yield: 7.8 mg (6.4 μmol), recovery: 58.2%).

The compound represented by General Formula (1) of the present inventionwas subjected to a physiological assay.

<Assay 1>

An assay on inhibitory effect against a DNA polymerase α was carried outin the following manner.

0.05 U of a DNA polymerase α purified and isolated from a bovine thymusby an immunoaffinity column was mixed with each of test compounds,sulfopyranosylacylglycerol (hereinafter, simply referred to as “SQAG”)derivatives, namely, SQAG 1, SQAG 2 and SQAG 3(listed in table 1)dissolved in DMSO. Each mixture was added with a buffer containinginorganic salts for the enzymatic reaction, [³H]-labeled dTTP andcompounds for reaction containing a template DNA strand, and incubatedat 37° C. for 60 minutes.

After the enzymatic reaction was quenched, the resultant reactionproduct was fixed on a dedicated filter and subjected to measurement bya liquid scintillation counter. The amount of enzymatically incorporateddTTP was calculated as a radiation dose (cpm) of [³H]. Note that, eachof the sulfopyranosylacylglycerol derivatives is a mixture of the S- andR-configurations with respect to an absolute configuration of the carbonof the 2-position of the glycerol moiety.

The results are shown as IC₅₀ in Table 1 below.

TABLE 1 Inhibitory activity on DNA polymerase α Com-

DNApoly-meraseinhibi-toryactivityIC₅₀ pound R₁₀₁ (μg/mL) SQAG1CH₃—(CH₂)₃—(CH═CH—CH₂)₁—(CH₂)₆—CO— 9.0 (14:1) SQAG2CH₃—(CH₂)₅—(CH═CH—CH₂)₁—(CH₂)₆—CO— 5.5 (16:1) SQAG3CH₃—(CH₂)₇—(CH═CH—CH₂)₁—(CH₂)₆—CO— 2.0 (18:1)

As is clear from Table 1, the compounds subjected to the assay exhibitsignificant inhibitory activity against the DNA polymerase α.

Colon cancer cells and gastric cancer cells used in the following twoassays are only for the purpose of illustration of cancer cells forwhich the medicinally active agent of the present invention effectivelyworks. Thus, cancer cells for which the medicament of the invention iseffective are not limited to these. Examples of other cancer cellsinclude those of esophageal cancer, gastric cancer, colon cancer,including those at colon and recta, thyroid cancer, bladder cancer,kidney cancer, prostatic cancer, malignant lymphoma, brain tumor, lungcancer, laryngeal cancer, pharyngeal cancer, hepatic cancer, gallbladdercancer, bile duct cancer, pancreas cancer, breast cancer, uterinecancer, ovarian cancer, vaginal cancer, leukemia, childhood cancer, skincancer, osteosarcoma, tongue cancer, cancer of small intestine, penilecancer, urethral cancer, ureteral cancer, testicular cancer, thymoma andmyeroma.

<Assay 2>

An assay on anticancer activity against cultured colon cancer cells wascarried out in the following manner.

Colon cancer cells DLD-1 were maintained and subcultured in RPMI 1640medium (containing 10% calf serum). Each of the test compounds (SQAG 2,SQAG 3 shown in Table 1) was suspended and diluted in the medium, andthen the cancer cells were cultivated together with the medium in a96-well plate at 3×10³ cells/well. After 48 hour cultivation, the MTTassay (Mosmann, T: Journal of Immunological Method, 65, 55-63 (1983))was carried out to compare survival rates.

The results are shown in FIG. 1.

In FIG. 1, open squares connected by a solid line indicate SQAG2 andopen circles connected by a solid line indicate SQAG3.

As is clear from FIG. 1, all of the sulfopyranosylacylglycerolderivatives have significant anticancer activities against the coloncancer cells used.

<Assay 3>

An assay on anticancer activity against cultured gastric cancer cellswas carried out in the same manner as in the assay 2 except that gastriccancer cells NUGC-3 were used instead of the colon cancer cells DLD-1.

The results are shown also in FIG. 1.

In FIG. 1, solid squares connected by a solid line indicate SQAG2 andsolid circles connected by a solid line indicate SQAG3.

As is clear from FIG. 1, the sulfopyranosylacylglycerol derivatives haveanticancer activities against the gastric cancer cells used.

<Assay 4>

Tests for human cancer-cell implanted mice were conducted in thefollowing manner.

5×10⁵ of human lung cancer cells A-549 cultured in an MEM mediumcontaining 5% calf serum were implanted in nude mice BALB/cAc1-nu. Thesize of the tumor formation site was periodically measured. When thesize of the tumor reached 30-50 mm³ (42 days after the implantation),the mice were subjected to an administration test.

Five mice were assigned at random to test groups and a control group. Atest compound (SQAG1, SQAG2 and SQAG3 listed in Table 1) suspended inPBS in a concentration of 100 μg/100 μL was administered to the testgroups, and PBS was administered to the control group at a dose of 100μL, every 3 days. This administration operation was repeated 8 times.The size of the tumor formation site was measured at all theadministration times. The volume of the tumor was calculated inaccordance with the following formula.Volume of tumor=tumor-site length×(tumor site width)²×0.5

The results obtained for the test compounds are respectively shown inFIG. 2 (SQAG1), FIG. 3 (SQAG2) and FIG. 4 (SQAG3).

In each Figure, the horizontal axis represents days after implantationof the cancer-cell and the vertical axis represents the volume of atumor.

It was demonstrated that each of the test compounds significantlysuppresses the formation of the tumor, compared to the control group.

No particular change was observed in the state of mice in the testgroups at the aforementioned dose. The mice were alive in the same stateas in the control group.

<Assay 5>

5×10⁵ of cultured lung cancer cells A-549 were subcutaneously injectedinto each of 7 week-old female nude mice BALB/cAc1-nu having 20-22 gweight, and the size of tumor was measured every 3 days from 37 daysafter the implantation. At 43 days after the implantation when the sizesof the tumor in all of the tumor-bearing mice reach 25-35 mm³, the micewere randomly divided into 7 groups of 4 mice for each. Of the 7 groups,one is used as a control group. 100 μL of PBS was subcutaneouslyinjected into the mice of the control group. To the remaining 6 groups,SQAG1 (14:1), SQAG2 (16:1) and SQAG3 (18:1) were subcutaneously injectedby dissolving each of the test compounds in 100 μL of PBS so as to givedoses of 4 mg and 20 mg per 1 kg weight. The injection was performedevery 3 days. This administration operation was repeated from 43 days to64 days after the cancer-cell implantation. The size of the tumor wasmeasured every 3 days until 70 days after the implantation. The volumeof the tumor was calculated in the same manner as in Assay 4.

The results obtained for the test compounds are respectively shown inFIG. 5 (SQAG1), FIG. 6 (SQAG2) and FIG. 7 (SQAG3).

In each of the test groups, it was demonstrated that the formation ofthe tumors is significantly suppressed compared to the control group.

After completion of the test, major organs, such as lung, heart,stomach, liver, pancreas, kidney, intestine and brain, of all the miceof each administration group were subjected to pathological evaluation,and no pathologically abnormality was observed in any organ.

As explained in the foregoing, according to the present invention, thereis provided a medicament containing at least one compound selected fromthe group consisting of sulfopyranosylacylglycerol derivativesrepresented by General Formula (1) and pharmaceutically acceptable saltsthereof, as an active ingredient.

Additional advantages and modifications will readily occur to thoseskilled in the art. Therefore, the invention in its broader aspects isnot limited to the specific details and representative embodiments shownand described herein. Accordingly, various modifications may be madewithout departing from the spirit or scope of the general inventiveconcept as defined by the appended claims and their equivalents.

1. A method for treating an adenocarcinoma cancer excluding coloncancer, lung cancer and gastric cancer, comprising administering to asubject in need thereof and suffering from said adenocarcinoma cancer, apharmaceutically effective amount of at least onesulfoquinovosylacylglycerol compound represented by formula (1):

wherein R₁₀₁ represents an acyl residue of an unsaturated higher fattyacid, and R₁₀₂ represents a hydrogen atom, and/or at least onepharmaceutically acceptable salt thereof.
 2. The method according toclaim 1, wherein said R₁₀₁ of formula (1) is represented by formula:R—C(═O)— wherein R is a straight-chain aliphatic unsaturated hydrocarbongroup having 13-25 carbon atoms and including 1-6 unsaturated bonds. 3.The method according to claim 2, wherein for R, the number of carbonatoms are odd numbers selected from the group consisting of 13, 15, 17,19, 21, 23 and
 25. 4. The method according to claim 2, wherein R₁₀₁ offormula (1) isCH₃—(CH₂)₃—(CH═CH—CH₂)—(CH₂)₆—CO—.
 5. The method according to claim 2,wherein R₁₀₁ of formula (1) isCH₃—(CH₂)₅—(CH═CH—CH₂)—(CH₂)₆—CO—.
 6. The method according to claim 2,wherein R₁₀₁ of formula (1) isCH₃—(CH₂)₇—(CH═CH—CH₂)—(CH₂)₆—CO—.
 7. The method according to claim 1,wherein the adenocarcinoma cancer is uterine adenocarcinoma cancer,breast adenocarcinoma cancer or pancreas adenocarcinoma cancer.